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The war of the sex chromosomes
Nathan A. Ellis
Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. e-mail: [email protected]
© 1998 Nature America Inc. • http://genetics.nature.com
With the publication of Ohno’s watershed
monograph1, molecular genetic characterization of the mammalian sex chromosomes has radically altered our view of
X-chromosome inactivation and the evolutionary conservation of synteny of the
mammalian X chromosome (Ohno’s law).
X inactivation is the dosage compensation
mechanism in mammals whereby during
embryogenesis of females a single X-chro-
ence of a functional Y homologue and
escape from X inactivation is remarkable;
these results confirm the prevailing theory
that Y deterioration is the driving evolutionary force behind the dosage compensation mechanism.
The evolution of the dosage compensation mechanism is inextricably interwoven
with the evolution of the mammalian sex
determination system and the formation
During the course of evolution, an ancestor to placental mammals must
have escaped a peril resulting from the hemizygous existence of all the
X-linked genes. Once this step was accomplished, the female no longer
needed two Xs in her somatic cells. Hence, the dosage compensation
mechanism by random inactivation of one or the other X evolved.
—Susumu Ohno
mosome is genetically silenced. Although
most genes are subject to X inactivation,
some escape. Moreover, during evolution
autosomal genes can be added to the X
chromosome and later incorporated to different extents into the inactivation system.
A recent report by Karin Jegalian and
David Page shows that inactivation of individual X-linked genes can evolve independently in different mammalian lineages2.
The general correlation between the pres-
of the Y chromosome (Fig. 1). The sex
chromosomes started out as a pair of ordinary autosomes. Once the Y chromosome
was elected to accumulate factors contributing to male fitness, a series of events
was initiated which culminated in a puny,
anarchic Y chromosome and a tightly
controlled, hierarchically regulated X
chromosome. Analogous to the Biblical
sequence in which order follows chaos, a
dosage compensation mechanism devel-
proto X proto Y
X
Y
PAR
F
pair of
ordinary
autosomes
inactive X
PAR
Müller's
ratchet
b
allelic system
of
sex determination
* mutation
single-dose
PAR
*
c
recombination
suppression
PAR
addition of
autosomal
material to
the PAR
dosage
compensation
XIST
off
XIST
on
*
PAR
PAR
PAR
Y
*
a
active X
PAR
*
*
testis-determining
gene is combined
with genes that
M increase male
fitness
oped in response to the mass destruction
of Y-encoded homologues. Genetic isolation of the Y led to the accumulation of
recessive mutations (a process known as
Müller’s ratchet) that, in aggregate,
reduced male fitness; this in turn ‘pressured’ the X chromosome to increase its
expression. Excessive X-gene expression is
presumed to have decreased female fitness
until the X-inactivation system evolved to
silence the doubly-dosed genes on one of
the X chromosomes in females.
The process by which a single X chromosome is selected for inactivation (Fig. 1) is
controlled by a single locus known as XIST
(ref. 3). Emanating from the XIST locus,
an inactivation signal is established that
spreads along the X chromosome. It was
once thought that almost every gene on the
X is inactivated; but it is now known that a
surprisingly large number (over 20, and
possibly many more) escape X inactivation4,5. Thirty years ago, only one escapee
gene had been localized to the distal tip of
the short arm of the X chromosome. Today,
we know of many such escapees, proximal
as well as distal, and on the long arm as well
as on the short—which indicates that
spreading of inactivation is a process mediated on a regional or gene-by-gene basis.
PAR
war between the sex
chromosomes; increased
X-gene dosage and
Y deterioration
d
*
*
regional
X-inactivation
XIST
on
XIST
off
*
e
X-autosome and Y-autosome
translocation that is
fertile and viable
double-dose
inactivated
The Ys and wherefores of sX chromosome evolution. Model for the evolution of the mammalian sex chromosomes. a, Mammalian sex chromosomes
evolved from a pair of ordinary autosomes. At first, sex was genetically determined by a simple diallelic system, F and M, in which the male was the heterogametic sex. b, Sex chromosome differentiation began when the proto-Y chromosome accrued at least one additional gene, that together with the M allele, conferred a selective advantage to males. Such combinations of syntenic genes in turn selected for a meiotic system in which recombination between sex
chromosomes was suppressed (a region of suppression is represented by the yellow area on the Y). c, The inevitable consequence of recombination suppression
was the additional accrual by the Y chromosome of recessive mutations (*) in the many genes unrelated to sexual development by a process known as Müller’s
ratchet. Recessive mutations in the recombination-suppressed segment are not effectively selected against, and patrilineal inheritance reduces the effective population size of Y genes, resulting in increased genetic drift. The loss in fitness in males that resulted from hemizygosity of more and more X chromosome genes
was corrected by increasing the expression of the X genes, thus raising the level of X-gene expression in females. A region has been maintained that is shared by
the sex chromosomes (denoted PAR for pseudoautosomal region). Crossing-over is confined to this segment and is required for the segregation of the sex chromosomes in male meiosis. d, Inactivation of one X chromosome in females evolved. A single locus, XIST, was recruited to initiate and signal genetic silencing of
one X chromosome in females (indicated by the larger arrows alongside the X chromosome). PARs in most eutherians are small regions, and in certain circumstances they can be dispensed with altogether (as in marsupials). On the other hand, PARs can be sites to which autosomal material can be translocated (e). The
newly translocated material then becomes subject to Müller’s ratchet and the dosage compensation wars.
nature genetics volume 20 september 1998
9
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© 1998 Nature America Inc. • http://genetics.nature.com
Table 1 • X-chromosome inactivation and Y-chromosome deterioration
Gene
ZFX
RPS4X
SMCX
Primates
Domesticated mammals
XCI
Y gene
XCIa Y geneb
no
yes
no
yes
no
yes
yes
no
no
yes
yes
noc
no
yes
yes
yese
Rodents
XCI Y gene
yes
noc
yes
no
no
yes
Marsupials
XCI Y gene
autosomald
yes
yes
aXCI,
© 1998 Nature America Inc. • http://genetics.nature.com
X-chromosome inactivation; yes, subject to X inactivation; no, escapes X inactivation;
blank, not known. bY gene, functional homologue on the Y chromosome; yes, homologue
present; no, homologue absent. cIn some cases, a Y gene may be present but either nonfunctional (no Y transcripts detected) or expression is reduced in level or restricted (the rodent Zfy
genes, which are expressed in testis only, have reduced homology to the highly conserved Zfx
genes, suggesting perhaps an evolving gene function). dZFX is autosomal in marsupials and in
monotremes, as described in the text. eGene is present, but expression unknown.
Paring PARs
On the human sex chromosomes, there is a
segment of 2.6 million base pairs on the
distal tips of the short arms (PAR1) where,
contrary to the usual prohibition, crossing-over during male meiosis is not only
allowed but required for successful segregation of the X and the Y chromosomes.
PAR1 genes are present in two doses in
both males and females, and they escape
X-inactivation. As such, it seems justifiable
that PAR genes are not subject to Ohno’s
legendary law. Similarly, a second PAR
(PAR2) exists on the distal tips of the long
arms where at least one gene is known to
disobey Ohno’s law. Even more illuminating is the fact that a huge portion of
the eutherian X chromosome originated as
chromosome material that was translocated in several pieces from several different autosomes sometime since the
evolutionary paths of eutherians and
metatherians separated about 150 million
years ago. The current human PAR1 is a
remnant of what was once a much larger
PAR (ref. 6). How did it shrink? As ever,
the expression and integrity of the sexchromosome genes provide a clue.
One formerly pseudoautosomal gene,
human STS, is only partially X-inactivated, whereas its Y homologue has
become a non-functional pseudogene.
Similarly, human PRKX escapes X inactivation; its Y homologue is intact but is
expressed at a lower level than the X
homologue. Thus, the dual processes of Y
deterioration and X inactivation have to
different extents integrated the formerly
pseudoautosomal genes into the sex chromosome system. What remains are X
genes in various intermediate evolutionary states. At one end of the spectrum are
X genes that are subject to inactivation
and have lost their functional Y chromosome counterparts, and at the other end
are X genes that escape X inactivation and
maintain functional Y counterparts.
Jegalian and Page have studied the genes
that, at least in humans, have resisted the
dual processes of Y deterioration and X
10
inactivation. As a suitable surrogate for
inactivation status, they analysed the
methylation levels in the promoter regions
of three genes, ZFX, RPS4X and SMCX, in
19 eutherian species representing 11 orders
(Table 1). The results were striking: ZFX
escapes X-inactivation, and a functional
homologue, ZFY, is maintained on the Y
chromosome in all mammals except
rodents. In rodents, ZFX is inactivated and
the expression level of ZFY is reduced and
and restricted to germ cells. RPS4X escapes
X inactivation only in the primate lineage;
everywhere else, RPS4X is X-inactivated.
Concomitantly, a functional RPS4Y homologue is maintained in the primate lineage
only. Finally, SMCX is X-inactivated in
some species and escapes inactivation in
others. SMCY gene sequences are present
in many species, but the available evidence
suggests that in species in which the X
gene is inactivated, Y gene function is
reduced. In mouse, inactivation of SMCX
occurs in embryogenesis but the gene partially reactivates during later stages of
development7. Mouse SMCX appears to
be in an intermediate state in which Y
function is normal but X inactivation has
not been completely successful.
These data demonstrate that the X-inactivation system has embraced these three
genes in some mammalian species but not
in others, and, wherever X inactivation is
observed, the expression of the homologue
on the Y chromosome is either reduced, or
the Y gene is lost entirely. If X inactivation
were driving these evolutionary events,
functional Y genes with X-inactivated
homologues would be more frequent.
Functional human Y genes have been thoroughly studied, and it is remarkable how
consistently their expression is either testisspecific or, alternatively, ubiquitous but
with a functional X homologue that escapes
X-inactivation8. Many are the defunct Y
genes that have X homologues that escape X
inactivation, and many are the X-inactivation escapees with no Y homologue at all.
From all the available evidence, we can conclude that, for the most part, Y deteriora-
tion is the driving evolutionary force. The
mouse SMCX gene, however, tells a cautionary tale; it shows that X inactivation can
be the driving evolutionary force.
X-inactivation escapees RPS4X and
SMCX were present on the X chromosome
ancestral to eutherians and metatherians
and ZFX was one of those genes translocated in the eutherian lineage to the X chromosome from an autosome6. Most of their
former colleagues were driven off the Y
chromosome long ago. What makes these
genes more resistant to the dual processes
of Y deterioration and X inactivation? Perhaps they resist the turns of Müller’s ratchet
because they are dosage-sensitive genes. In
other words, mutation or X inactivation of
one copy of these genes may result in negative phenotypic effects (for example,
growth or fertility defects). This hypothesis
could be testable by generating a mouse
deficient of SMCX. Supporting it is the fact
that somatic features resembling those of
people with Turner syndrome have been
observed in females with XY gonadal dysgenesis who have deletions of ZFX and
RPS4X, suggesting that these genes may
indeed be dosage sensitive. How Y deterioration and X inactivation would capture dosage-sensitive genes in some
mammalian lineages but not others is
unknown; perhaps the two processes occasionally pounce simultaneously on a gene,
or perhaps modulations of autosomal
genes that control dosage sensitivity suddenly confer dosage resistance.
The mammalian X inactivation system
has turned out to be far more malleable
and adaptive then originally imagined.
Inactivation is controlled on both a chromosome-wide and a gene-regional basis,
and X-inactivation status continues to
evolve even today as new genes are shuffled into the PAR and later captured by the
non-recombining part of the Y chromosome. Once capture has been effected,
Müller’s ratchet proves to be an exceptionally strong force—to which the vast number of Ohno-obedient X-inactivated genes
testify. While the Y chromosome stands
accused of violence to many decent, hardworking genes, at least some of us can be
thankful that, although it may not be
much, it’s good at what it does.
■
1. Ohno, S. (Springer-Verlag, Berlin, 1967).
2. Jegalian, K. & Page, D.C. Nature 394, 776−780 (1998).
3. Carrel, L. & Willard, H.F. Nature Genet. 19, 211−212
(1998).
4. Disteche, C. Trends Genet. 11, 17−22 (1995).
5. Brown, C., Carrel, L. & Willard, H.F. Am. J. Hum.
Genet. 60, 1333−1343 (1997).
6. Graves, J.A.M., Disteche, C.M. & Toder, R. Cytogenet.
Cell Genet. 80, 94−103 (1998).
7. Lingenfelter, P.A. et al. Nature Genet. 18, 212−213
(1998).
8. Lahn, B.L. & Page, D.C. Science 278, 675−680 (1997).
nature genetics volume 20 september 1998